11
Optimal Pharmacokinetics of Cyclosporine and Tacrolimus Based Relationship Among
AUC, Trough and Peak Concentration
Hironori Takeuchi Department of Practical Pharmacy,
Tokyo University of Pharmacy and Life Sciences, Tokyo Japan
1. Introduction
Calcineurin inhibitors (CNIs) are maintenance immunosuppressive drugs that have been used as the main therapy for organ transplantation for many years. Of the CNIs, cyclosporine (CYA) and tacrolimus (TAC) are used in clinical practice. The CYA binding protein is cyclophilin and that of TAC is FK-binding protein (FKBP), but both drugs have same mechanism of action: the inhibition of interleukin 2 (IL-2) production by binding the binding protein complex to calcineurin (CN). It is thought that the area under the concentration time curve (AUC) for both drugs may be the pharmacokinetic (PK) parameter that is the most associated with clinical effect. However, oral CYA administration gave a blood concentration–time curve with a high CYA peak concentration (Cp), and oral TAC showed a gradual blood concentration–time curve, keeping at the minimum of the therapeutic range; both drugs vary significantly in their pharmacokinetics1). The Cp of CYA has increased since the Neoral® preparation of CYA was used, compared with Sandimmune®, whereas the Cp of TAC decreased since using a sustained release preparation; thus the differences between CYA and TAC are considerable2). Although the optimal pharmacokinetics of both drugs may be similar to those of other drugs with the same mechanism of action, no conclusions have been reached on whether the peak blood concentration, or a specific maintained blood concentration, is required for CNI pharmacokinetics, even if both drugs show identical AUCs. In addition, although CYA and TAC are similar CNI drugs, there are differences in the recommended monitoring points of CYA and TAC; these points are the C2 level (the blood concentration 2 h after oral administration), which mainly reflects Cp, and the trough concentration (Ct)3-8), respectively9-
11). To solve these problems, it is necessary to consider comprehensively not only AUC, but also Cp, Ct, and time above the minimum effective concentration (%T > MEC). We discuss the optimal pharmacokinetics of CNIs by comparing various aspects of CYA and TAC.
2. Which parameter is the most closely associated with clinical results?
2.1 Cyclosporine
It is a well-known fact that Ct is associated with clinical effect. As when the Ct become higher, the AUC and the Ct p are consequently higher. it is not surprising that Ct, Cp, and
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AUC are all correlated with clinical effect. The question, therefore, is which of these PK parameters is the most associated with clinical effect. It is commonly thought that the AUC of CYA is most closely associated with clinical effect12,13). However, it is often difficult to measure AUC0–12 for 12 h after administration in clinical practice. Accordingly AUC0–4 (the area under the concentration time curve at 0–4 h following oral administration) is generally used as an alternative absorption phase to AUC0–12. This earlier blood sampling point that has been used since the introduction of cyclosporine microemulsion preconcentrate (Neoral), in which oral absorption is significantly stabilized3,14,). Even AUC0–4 requires several blood sampling points, and this causes problems such as increased burden on patients, cost, and medical staff duties. It has therefore been recommended that a single blood sampling point, C2, be used; this is the sampling point at which the majority of patients show peak level in the absorption phase, and is better correlated with AUC0–12 than C03-8). It has been reported that AUC0–4 and C2 are associated with the incidence rate of acute rejection and nephropathy or similar conditions3,15-19), and a relationship with clinical effects and side effects was demonstrated. Nevertheless, there are several problems relating to the use of C2 because its determination involves the measurement of absorption values. As it means the change in blood concentration over time is great; there is a possibility that C2 may vary significantly over a small interval in blood sampling times, in comparison with trough value 20,21), and complicated procedures for outpatients are increased. Given the above, the monitoring of C2 in routine clinical practice is questionable 22,23), and it has been reported that there is little evidence in which it is useful to monitor C224).
2.2 Tacrolimus
On the other hand, the AUC of TAC, like that of CYA, is commonly considered to be a parameter which is highly associated with clinical effect, despite little evidence for TAC treatment showing clinical effects such as acute rejection25,26)or side effects such as
nephrotoxicity27). Therefore, TAC was examined to show which blood sampling point is the best correlated with AUC as CYA. One study reported that Co is the best correlated with AUC27), whereas another study suggested that a formula with fewer blood sampling points, and not Co, is the most closely correlated with AUC (limited sampling strategy) 28-31).
Thus, although the AUC of CNIs is regarded as the PK parameter, which is the most closely associated with clinical effect, its monitoring point is not clear. In addition, it has not been much discussed whether the peak blood concentration, or a specific maintained blood concentration, is required for pharmacokinetics even if both drugs show identical AUC. For the purpose of solving this problem, the authors analyzed the pharmacokinetics of CYA and TAC by comparing AUC, Cp, and Ct parameters, used not as independent parameters but in a new manner, which could indicate the interrelationship between these parameters.
2.3 Comparison between pharmacokinetics of oral cyclosporine and tacrolimus1)
There has been no study comparing the differences between the blood concentration time curves of CYA and TAC in detail. Therefore, the authors thought that the pharmacokinetics of both drugs could be compared by using the blood concentration (C/D/BW), adjusted for dose per body weight. Although the AUC/(D/BW) of both CYA and TAC, which should show the relative availabilities, was equal, the Cp/(D/BW) of CYA was comparatively higher than that of TAC and, on the other hand, the Ct/(D/BW) of CYA was lower than that
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of TAC, which illustrated a blood concentration time curve with a sharp peak. On the other hand, the pharmacokinetics of TAC showed that the Cp/(D/BW) of TAC was lower and the Ct/(D/BW) was higher, which illustrated a gently hunched blood concentration time curve, which was similar to the curve for continuous intravenous infusion (Figure 1, Table 1).
ケ
ゲケケ
コケケ
ゴケケ
サケケ
ザケケ
シケケ
ケ コ サ シ ス ゲケ ゲコ
Time after administration ォhオ
ッlood concentration per
dose per body w
eight ォngグm
lオグォm
gグkgオ
Tヂツ
ツYヂ
膅Takeuchi H. Biol Pharm Bull. 2008 䐢
Fig. 1. Comparison of the mean blood concentration-time curves for CYA (n=20) and TAC (n=24)
CYA TACp value
(n = 20) (n = 24)
AUC/艜/艗W(ng/mL・h)/(mg/kg) 2323±447 2507±1255 N.S.
Cp/C
t6.00±1.78 1.93±0.43 <0.0001
𦪌p/艜/艗W
(ng/mL)/(mg/kg) 433.1±90.3 292.6±135.7 <0.005
Ct/艜/艗W
(ng/mL)/(mg/kg) 77.1±23.6 160.0±91.8 <0.005
AUTL/AUC膅%) 41.9±6.9 73.4±8.1 <0.0001
膅Takeuchi H. Biol Pharm Bull. 2008 䐢
Table 1. Comparison of pharmacokinetic parameters between CYA and TAC
Thus, even if the AUC of both drugs were equal, the pharmacokinetics of the both drugs is totally different, from the viewpoint of the correlation with each peak value and each trough value. We developed AUTL/AUC% (percentage of the area under the trough level in the
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area under the blood concentration) in order to assess the interrelationship between AUC, Cp, and Ct in comparing CYA and TAC (Figure 2). As a result, the AUTL/AUC% of CYA was as low as 41.9%, and the AUC had a higher percentage of dependence on Cp than on Ct. On the contrary, the AUTL/AUC% of TAC was as high as 73.4%, and the AUC had a higher percentage of dependence on Ct than on Cp (Figure 3).
Blo
od c
once
ntr
atio
n膅n
g/m
L)
Time
0
ツp
ツt
ヂUツpo
ヂUTネ
t
ヂヂTネ
%T > MEC舢time above minimum effective concentration
AUTL舢area under the trough level
AATL舢 area above the trough level
AUTL/AUC%舢a ratio accounting for AUTL in AUC
MEC%T > MEC
Takeuchi H. Organ Biology (Jpn) 2009
Fig. 2. Blood concentration curve and pharmacokinetic parameters
ケ
ゲケケ
コケケ
ゴケケ
サケケ
ザケケ
シケケ
ジケケ
スケケ
ズケケ
ゲケケケ
ケ ゲ コ ゴ サ ザ シ ジ ス ズ ゲケ ゲゲ ゲコ
Time after administration ォhオ
ツY
ヂb
lo
od
co
nc
en
tr
at
io
nォn
gグ
mネ
AUTL
ヂUTネグヂUツ; サゲクズ±シクズ ォ%オ
ヂUTネグヂUツ; サゲクズ±シクズ ォ%オ
ツYヂ
ケ
ザ
ゲケ
ゲザ
コケ
コザ
ケ ゲ コ ゴ サ ザ シ ジ ス ズ ゲケ ゲゲ ゲコ
Time after administration ォhオ
Tヂ
ツb
lo
od
co
ce
nt
ra
tio
nォn
gグ
mネ
オ
AUTL
ヂUTネグヂUツ; ジゴクサ±スクゲ ォ%オ
ヂUTネグヂUツ; ジゴクサ±スクゲ ォ%オ
Tヂツ
(n = 20) (n = 24)
膅Takeuchi H. Biol Pharm Bull. 2008 䐢
AATL
AATL
Fig. 3. Comparison of the pharmacokinetic parameters of AUTL/AUC% between CYA and TAC.
To demonstrate these results further, we examined the correlation between the AUC and the area above trough level (AATL) or AUTL, and found that these results were consistent with
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the theory that CYA had higher correlation with AATL, and TAC had higher correlation with AUTL (Table 2). If AUC is most closely associated with clinical effect, it may be appropriate to monitor Cp and Ct for CYA and TAC, respectively. However, considering that the blood concentration per unit time for Cp changes dramatically, and taking into account the measurement convenience and complexity of the methods, it is thought that TAC to measure Ct is preferable as a drug to perform TDM than CYA to recommend measuring C2. However, it is thought that Ct as monitoring paint is not a clinical problem, as the measurement of CYA Ct reflects the AUC adequately.
Table 2. Comparison of correlation coefficients between AUC and AUTL or AATL in CYA- and TAC-treated recipients
Furthermore, the influences on clinical effect, such as effectiveness or side effects, would be different between pharmacokinetics with a higher peak value, namely with low AUTL/AUC% and pharmacokinetics with a maintained minimum effective concentration, namely with high AUTL/AUC%, such as the blood concentration of continuous intravenous infusion, even if the AUC of both drugs were equal. By illustrating this, as shown in Figure 4, it is possible to see a difference between the pharmacokinetics of A and B, even if both AUCs are equal. The Cmax of A is lower than that of B but the Cmin of A is higher than that of B. This relation can be applied to the correlation of CYA and TAC discussed above. In addition, considering PK parameters involved pharmacodynamics (PD) such as the minimum effective concentration (MEC), A may maintain MEC over a certain time (%T > MEC), which is longer than for B, even if the AUCs for both A and B are equal. CNIs may be a drug for which time above MIC (MEC) is associated with drug efficacy, as is the case with antimicrobial agents such as beta-lactam antibiotics, This suggests that the effects of A and B may be different, by the correlation of AUC, Cp, and Ct.
Thus, the examination of clinical effect using only AUC is limited, and therefore, an analysis including the interrelationship between AUC, Cp, Ct, and time is required.
3. Correlations among AUTL/AUC%, effects, side effects, and PK parameters for other drugs practicing TDM
Table 3 shows the results of correlations among the PK parameters, effects, and side effects of current drugs investigated for TDM in the literature. As a result, the blood concentration time curves can be classified into the following categories: a drug group showing a sharp peak curve (AUTL/AUC < 50%, Cp/Ct > 6), such as aminoglycoside antibiotics (AGs), and a drug group showing a gentle peak curve (AUTL/AUC% > 60%, Cmax/Cmin < 2), such as
antiarrhythmic drugs, bronchodilators, and anticonvulsant drugs (Figure 5).
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AUC舢A=B
Cp舢 A<B, Ct舢 A>B, MEC time: A>B
a
b
a
b
A B
Blo
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once
ntr
atio
n
Time
ケ
ゲケケ
コケケ
ゴケケ
サケケ
ザケケ
ケ コ サ シ ス ゲケ ゲコ
Time after administration ォhオ
ッlood concentration per
dose per body w
eight ォngグm
lオグォm
gグkgオ
Tヂツ
MEC
ケ
ゲケケ
コケケ
ゴケケ
サケケ
ザケケ
シケケ
ケ コ サ シ ス ゲケ ゲコ
Time after administration ォhオ
ッlood concentration per
dose per body w
eight ォngグm
lオグォm
gグkgオ
ツYヂ
tt
Takeuchi H. Organ Biology (Jpn) 2009
Fig. 4. Pattern diagrams in the case that Cp, Ct, and MEC time are different, even though AUC is the same.
drug ヂUTネグヂUツ% ツpグツ
t
efficacy
parameter
side effect
parameter
ツyclosporine ノテPツ
カ
サゲクズ±シクズ シクケ±ゲクス ヂUツケギサ
、ツコ、ツt ヂUツ
ケギサ,ツ
コ,ツt
Tacrolimus ジゴクサ±スクゲ ゲクズ±ケクサ ツt
ツt
ヂmikacin
カ
ォinjectionオ ゲシクザ ゲサクサ ツmax ツt膅ツmax䐢
Vancomycin
カ
ォinjectionオ コズクス ゲゲクゲ ツt ツt膅ツmax䐢
Teicoplanin
カ
ォinjectionオ サジクゲ シクケ ツt ツt
ヅisopyramide ジシクス ゲクジ
Procainamide シザクゲ ゲクズ
ノexiletine ジゲクシ ゲクス
ズケクサ ゲクコ
ジザクズ ゲクジ
ズケクザ ゲクゴ
ジコクサ ゲクズ
スケクジ ゲクザ
ジジクシ ゲクザ
スコクジ ゲクザ
カヂUTネグヂUツ%舼ザケ%、ツmaxグツmin>シ
ツt
maintenance of
effective blood
concentration
ツt
Theophylline
Sodium valproate
Takeuchi H. Organ Biology (Jpn) 2009
Table 3. AUTL/AUC%, Cp/Ct, and parameters of the efficacy and side effect of drugs that are used in therapeutic drug monitoring (TDM)
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Optimal Pharmacokinetics of Cyclosporine and Tacrolimus Based Relationship Among AUC, Trough and Peak Concentration
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Blo
od
dru
g c
on
cen
trat
ion
Time Time
Range of side
effects
Effective range
Aminoglycosides (AGs) Drugs except ヂGs
Blood concentration curve of drugs
to decrease blood concentration once
to avoid side effects
Blood concentration curve of drugs to
maintain minimum effective concentration
AUTL/AUC% is small
Cp/Ct is high AUTL/AUC% is small
Cp/Ct is high
AUTL/AUC% is large
Cp/Ct is lowAUTL/AUC% is large
Cp/Ct is low
A BAUTL
AUTL
Effective range
Range of
side effects
Fig. 5. Two patterns of blood concentration curve based on AUTL/AUC%Takeuchi H. Organ Biology
(Jpn) 2009
Fig. 5. Two patterns of blood concentration curve based on AUTL/AUC%
All drugs except AGs, glycopeptide antibiotics, and CYA, which required AUTL/AUC%
≥60% and Cp/Ct ≤2 to maintain the therapeutic range, had a gentle blood concentration
time curve and the monitoring point was Ct. It is preferred that AGs maintain a
concentration to the peak value for as long as possible, but it must be reduced to below a
specific blood concentration on a temporary basis to avoid nephrotoxic side effects.
Therefore, AUTL/AUC% decreased to a low level and Cp/Ct increased to a high level to
show a blood concentration time curve with a sharp peak. Furthermore, AGs have a post-
antibiotic effect (PAE), so that it can maintain its effect even if it falls below the
therapeutic range.
Furthermore, the pharmacokinetics of AGs and glycopeptide antibiotics relate to
administration by injection, and these drugs are not required to control a clinical condition
for a long period. Therefore, the results showed that CYA (Neoral) was the only oral drug
used for prevention of a long-term pathologic condition that showed a sharp peak curve.
Drugs with a sharp peak concentration were the only drugs for which the blood
concentration needed to be reduced on a temporary basis to avoid side effects, and there
was no drug that needed to be at peak concentration in order to have an effect. However,
when the CYA used was switched from Sandimmune to Neoral to increase and stabilize
absorption, the absorption rate constant (Ka) became large such that the peak value
necessarily increased, and the AUTL/AUC% decreased.
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CYA may not require higher peak concentration, if the trough concentration can be higher to keep the AUC, although it is impossible that raising the trough value and decreasing the peak value (to increase the AUTL/AUC%) using the existing CYA formulation, keep the AUC.
4. Optimal pharmacokinetics based on PK/PD analysis
In connection with the preceding paragraph, regarding patients treated with CYA (Neoral), it has been reported that the inhibitory action of CN was in proportion to the blood concentration following administration32), and that IL-2 was stably suppressed at the peak value rather than the trough value33). On the other hand, another report showed that TAC above a certain level continuously had an inhibitory action of CN after administration34). It is possible that the differences between the both drugs may contribute to these results (Figure 6). In other words, CYA shows sufficient CN inhibitory action at the peak value, but the data suggests that the CN inhibitory action may be insufficient at the trough value. On the other hand, TAC is at a concentration that shows a certain level of CN inhibitory action throughout all time points, including the trough value, which suggests that it may always show inhibitory action of CN above a certain concentration.
ケ
コケ
サケ
シケ
スケ
ゲケケ
ゲコケ
ケ ゲ コ サ ズシ
Time
ツハ
activity ォ%オ
ケ
コケケ
サケケ
シケケ
スケケ
ゲケケケ
ゲコケケ
ツYヂ
concentration (n
g/m
L)
% calcineurin activity
blood level ォngグmネオ
Halloran P, Focus on Medicine, No. 13, 1998
ケ
コケ
サケ
シケ
スケ
ゲケケ
ゲコケ
ケ ゲ コ ゴ サ シ
Time
ツハ
ac
tivit
y (
%)
ケ
ゲケ
コケ
ゴケ
サケ
ザケ
シケ
Tヂ
ツconcentration ォngグm
ネオ
Pernille B et al., Transplant 2001: Abstract #1076,
Takeuchi H. Organ Biology (Jpn) 2009
Fig. 6. Relationship between blood concentration and calcineurin activity in CYA and TAC.
The authors analyzed the relationship of the concentration—lymphocyte proliferation rate curves (PD) of CYA and TAC with the target blood concentration (PK) and found that lymphocyte proliferation was completely suppressed at the trough level of TAC. On the other hand, CYA had a low inhibition ratio at the trough value and was more than sufficient inhibited at the peak value, so that there was no need for the concentration to be as high as the peak value in terms of pharmacodynamics; consequently, it was necessary to make the trough value higher (Figure 7).
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ケ
コケ
サケ
シケ
スケ
ゲケケ
ゲコケ
ケクケケゲ ケクゲ ゲ ゲケ ゲケケ ゲケケケ ゲケケケケ
ツalcineur in inhibitor concentrat ion ォngグmネオ
Suppressive rate of lym
phocyte proliferation
ォ%オ
ツYヂ 膅ハ = コジオ
Tヂツ 膅ハ = コシオ
Tヂツ
target
trough
range
ツYヂ
target
trough
range
ツYヂ
target
peak
range
Therapeutic trough range 5~10 ng/mL 50~250 ng/mL
Lymphocyte proliferation
was completely suppressed
in the target trough range.
Lymphocyte proliferation was not
completely suppressed in the
target trough range.
Takeuchi H. Organ Biology (Jpn) 2009
Fig. 7. Relationship between average concentration-lumphocyte proliferation rate curves and target blood concentration of calcineurin inhibitors.
5. Optimal blood concentration for continuous intravenous infusion based on AUC
Currently, intermittent intravenous administration and 24-h continuous intravenous administration can be compared for optimal pharmacokinetics in clinical practice.
For patients undergoing hematopoietic stem cell transplantation, drugs are administered by
intravenous injection for relatively long periods, from several weeks to several months,
because ingestion is not possible. However, the theoretical optimum targeted blood
concentration for continuous infusion has never been clearly determined. If AUC is the
parameter most closely associated with clinical effect, it can be considered correct, in theory,
to adjust the blood concentration of oral and intravenous administration to the level that
achieves the same AUC. We used the AUTL (area under trough level) parameter developed
by the authors to calculate the target blood concentration for continuous intravenous
infusion from the trough level for oral administration35,36). As a result, the target blood
concentration for continuous intravenous infusion of TAC (Css) was 1.4 times that of the Ct
because AUTL/AUC% is large. These results were almost close to the blood concentration
in the present practice of continuous intravenous infusion. Meanwhile, CYA has a small
AUTL/AUC% so that a trough value 2.55 times higher and a considerably high Css were
required in theory (Figure 8).
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Blo
od c
once
ntr
ate
level
膅ng/m
L)
Time (h)0 12
ツmax
ツtヂUツ
po
ヂUTネ
ツss
ヂUツ菔v
AUCpo= AUCiv→CSS = Ct×膅AUCpo/AUTL䐢
Formula for calculating Css from Ct
Ex𦨞Ct
(ng/mL) Css (ng/mL)
TAC 舢Css = Ct×1.40 10 14
CYA舢Css = Ct × 2.55 200 510
Nakamuka Y, Transplant Proc, 2005
Fig. 8. Formula for calculating Css from Ct, and the relationship between the AUC of oral administration and continuous intravenous infusion.
In actual hematopoietic stem cell transplantation, it has been reported that continuous
intravenous infusion of CYA at 250–400 ng/mL Css, which is lower than the theoretical
value, showed lower nephrotoxicity than intermittent intravenous administration twice a
day, and that the incidence rate of acute graft-versus-host disease (GVHD) was high37).
However, in a study by the same group, comparing a 300 ng/mL Css group with a
500 ng/mL Css group, it was reported that the incidence rates of acute and chronic GVHD
were significantly lower in the 500 ng/mL group, and there was no difference in side effects,
such as nephrotoxicity, between both groups of the trial38). In another study by Miller et al.
using a Css of 450–500 ng/mL, similar results on acute GVHD and tolerability were
reported39) and these reports were consistent with the authors’ hypothesis. Continuous
intravenous infusion is the ultimate method for maintaining a minimum effective
concentration (Figure 4-A), and it may be possible for the pharmacokinetics to have no peak
if the AUC of CYA can be obtained; in other words, the pharmacokinetics as minimum
effective concentration is maintained.
Meanwhile, in many institutions, patients undergoing hematopoietic stem cell transplantation received different dosages, such as 3 mg/kg/day twice a day (3 h continuous infusion) by I.V. infusion, once a day (4 h continuous infusion) by I.V. infusion, once a day (10 h continuous infusion) by I.V. infusion, and 24 h continuous intravenous. However, there are slight differences in the clinical results40). Each AUC was
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almost the same, at around 11,000 ng·h/mL, in all the dosages above, but the results calculated by the authors revealed that each AUTL/AUC% was approximately equal (35–44%) in intermittent administration and it was 100% in continuous intravenous infusion (Figure 9). Moreover, we set various therapeutic ranges to simulate and calculate %T > MEC and found that the values significantly varied depending on MEC (Figure 10). These results suggest that CYA has a wide tolerance of blood concentration in terms of action and side effects, and that all dosages might be clinically equal.
Fig. 9. Comparison of pharmacokinetic parameters among various administration methods of CYA in hematopoietic stem cell transplants.
For TAC, it has already been shown in a clinical trial that numerous side effects, such as nephropathy or neurologic symptoms, are caused by twice daily intermittent intravenous administration. Therefore, the package insert indicates that it should be administered by 24 h continuous intravenous administration, and it is known that continuous intravenous administration is appropriate. It may be because the method for oral use has a large AUTL/AUC% and no high peak, whereas intravenous injection twice a day by high speed drip has a high peak. It is considered that the effect range and the side effect range of TAC
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may be closer than those of CYA and that pharmacokinetics showing a gentle blood concentration time curve (large AUTL/AUC%) may be suitable.
ノテツ コサギhツIV サ h×ゲ pクoク×コカ
ゴ h×コ ゲケ h×ゲ
ゴケケ ngグmネ ゲケケ% ジゴ% シズ% シズ% シズ%
サケケ ngグmネ ゲケケ% シゲ% ザサ% ザゲ% サゴ%
ザケケ ngグmネ ゲケケ%カ
ザゲ% サコ% ゴシ% コジ%
500 ng/mL
400 ng/mL
300 ng/mL
high low
15
MEC
Fig. 10. T%>MEC of various CYA administration methods for each MEC in hematopoietic stem cell transplants.
6. Pharmacokinetic differences between morning and evening
In studies monitoring the blood concentration of CYA and TAC for 24 h and comparing
the pharmacokinetics of morning and evening, some studies reported that there was no
difference in pharmacokinetics between morning and evening41,42), whereas several other
studies reported that there was a difference43-45). In the authors’ data, the AUC0–12, AUC0–4,
C2, and Cmax following evening administration were significant lower than those
following morning administration both in patients treated with CYA and patients treated
with TAC46,47) (Figure 11). As TAC shows gradual blood concentration–time curve in
comparison with CYA, TAC is hardly affected by delayed or reduced absorption in the
evening, so that the differences between various PK parameters between morning and
evening were smaller in TAC (Table 4). Therefore, a drug such as TAC, which shows
pharmacokinetics with a large AUTL/AUC% may have potential benefits because it has
little difference in pharmacokinetics between morning and evening. However, a sustained
release preparation of TAC administered once a day has been launched and its
pharmacokinetics has no peak value in the evening because it is administered only in the
morning, but its efficacy is equal to that of a drug administered twice a day. From this
fact, it is possible that the pharmacokinetic difference between morning and evening is
not a clinical problem.
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0
200
400
600
0 4 8 12 16 20 24
Dru
g b
loo
d c
on
ce
ntr
atio
n/D
os
e/B
od
y w
eig
ht
[(n
g/m
L)/
(mg
/kg
)]
CYA (N = 35)
TAC (N= 28)
Time (h)
24 hours between CYA and TAC. p.o p.o
Morning(8:00 AM) (8:00 PM) Evening
Fig. 11. Comparison of blood concentration-time curves through 24 hours between CYA and TAC.
Tヂツォn=ゲコオ ツYヂォn=ゲケオ P値
ヂUツケギゲコ
膅ng・hrグmlオ ケクズゲ±ケクゲケ ケクジジ±ケクゴゲ ケクケケジゴ
カ
ヂUTネグヂUツォ%オ ゲクココ±ケクゲス ゲクサコ±ケクコジ ケクケザゴス
ヂUツケギサ
膅ng・hrグmlオ ケクジサ±ケクゲサ ケクザシ±ケクゲズ ケクケゲササ
カ
ツコ膅ngグmlオ ケクジケ±ケクゴゲ ケクザゲ±ケクコザ ケクゲゴスコ
ツmax膅ngグmlオ ケクジズ±ケクコシ ケクザザ±ケクゲサ ケクケゲシゲ
カ
ツmin膅ngグmlオ ゲクゲジ±ケクコゲ ゲクコス±ケクゴケ ケクゴゲゴゲ
ツmaxグツmin ケクジゲ±ケクゴコ ケクサザ±ケクゲシ ケクケゴサゴ
カ
Tmaxォ菐r䐢 コクシジ±ゲクサコ ゲクシゴ±ケクスケ ケクケコスジ
カ
Table 4. Comparison of pharmacokinetic parameter ratios of evening to morning administrations between TAC and CYA
p.o p.o
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7. Calculation of optimal dose and blood trough concentration on switching between CYA and TAC
The authors calculated the optimal dose and the Ct concentration on switching between CYA and TAC, with a comparison of the pharmacokinetics (AUC, Cp, and Ct) of CYA and TAC. AUC/D/BW is equal, but the Ct of TAC is relatively higher than that of CYA as a result of the pharmacokinetic differences; considering this, the dosage ratio is as follows: CYA:TAC = 25:1, and the targeted Ct ratio is as follow: CYA:TAC = 13:148,49) (Figure 12). These reduced values were equal to the titer ratio calculated from the IC50 value of the PD data.
Fig. 12. Conversion rate of dose and target trough level derived from pharmacodynamic and pharmacokinetic analyses.
8. Conclusion
Although both CYA and TAC belong to CNIs and the availabilities (AUC/D/BW) are the same, significant differences in the pharmacokinetics (blood concentration-time curve) of both drugs were found. Given that the AUC is the parameter that is most closely associated with clinical effect, it is optimal to monitor Cp and Ct for oral CYA and TAC, respectively.
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Optimal Pharmacokinetics of Cyclosporine and Tacrolimus Based Relationship Among AUC, Trough and Peak Concentration
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However, even if both drugs show identical AUC, the clinical effects, such as effectiveness or side effects, may vary according to differences in the blood concentration time curve based on the relative correlation of Cp and Ct. From the report on inhibitory action of CN and blood concentration32) and the results of PK/PD analysis, It is also thought that CYA status is shown in Figure 13-A. On this basis, it is supposed that the clinical effect of CYA is slightly lower than that of TAC50-52). It is plausible that the Ct of CYA can be reduced on a temporary basis to avoid nephrotoxicity, as is done with AGs (Figure 13-A). Conversely, there is a possibility that Cp is associated with side effects as shown in Figure 13-B. CYA can reduce the Cp (Figure 13-D) and can also keep the AUC in the blood concentration time curve to elevate the Ct. In fact, CYA shows good results by continuous intravenous infusion for hematopoietic stem cell transplantation38). However, it has been found that there is a slight difference in the clinical results of the hematopoietic stem cell transplantation40) (Figure 14). Therefore, CYA has wide tolerance of blood concentration, even if it is administered at various dosages or if it has various blood concentration time curves.
Effective range Range of side effects
CYA TAC
C
Effective range Range of side effects
CYA TAC
D
Effective range Range of side effects
CYA
TAC
B
Side effects
Blo
od
con
cen
trat
ion Effective range Range of side effects
CYA
TAC
A
Lack of efficacy
Avoidance of side effects
Tolerance range
Blo
od
con
cen
trat
ion
Blo
od
con
cen
trat
ion
Blo
od
con
cen
trat
ion
Various relationships of blood concentration curve and the effective and side effect ranges, when AUCs are
nt. Takeuchi H. Organ Biology (Jpn) 2009
Fig. 13. Various relationships of blood concentration curve and the effective and side effect ranges, when AUCs are equivalent.
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CYA and TAC are used equally in clinical practice in terms of the existing therapeutic dose and the AUC, and there are no particular problems (Figure 13-C). On the other hand, it is thought that a gentle (with AUTL/AUC% high) blood concentration time curve is suitable for TAC because its tolerance level is low (Figure 14).
Blo
od
con
cen
trat
ion
Effective
range
Range of CYA side effects
4-h DIV×1 3-h DIV×2 10-h DIV×1 24-h CIVPO ×2
Range of TAC side effects
PO ×2 24-hCIV
CYA TAC
Takeuchi H. Organ Biology (Jpn) 2009
Fig. 14. Difference in range of effective and side effect bllod concentrations between CYA and TAC.
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Readings in Advanced Pharmacokinetics - Theory, Methods andApplicationsEdited by Dr. Ayman Noreddin
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This book, "Readings in Advanced Pharmacokinetics - Theory, Methods and Applications", covers up to dateinformation and practical topics related to the study of drug pharmacokinetics in humans and in animals. Thebook is designed to offer scientists, clinicians and researchers a choice to logically build their knowledge inpharmacokinetics from basic concepts to advanced applications. This book is organized into two sections. Thefirst section discusses advanced theories that include a wide range of topics; from bioequivalence studies,pharmacogenomics in relation to pharmacokinetics, computer based simulation concepts to drug interactionsof herbal medicines and veterinary pharmacokinetics. The second section advances theory to practice offeringseveral examples of methods and applications in advanced pharmacokinetics.
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